DK169549B1 - Pyrimidoindoles, their preparation and pharmaceutical composition containing them - Google Patents

Description

in DK 169549 B1

The present invention relates to novel substituted pyrimidoindoles, to a process for their preparation, and to pharmaceutical compositions containing these compounds.

5 In GB Publication No. 1,366,133, there are, inter alia, disclosed tetrahydropyrimido [1,2-a] indoles, have hypoglycemic activity. The pyrimido ring in the tetrahydro-pyrimido [1,2-a] indoles is preferably unsubstituted, but may be substituted by a single hydroxy group or one or two lower alkyl groups. In contrast, the ring of the compounds of the present invention is substituted by a spiral group at the 3-position, as set forth in formula (I) hereinafter.

The compounds of GB specification which are structurally closest to the novel compounds of the invention are the gem dialkyl substituted compounds, but there is no chemical or biological basis for considering the indication of gem dialkyl substitution as a teaching or suggestion, resp. an incentive to prepare a compound with spiroalkane substitution, especially in the field of hypoglycemically active compounds; since spiroalkane substitution is not widely known in the hypoglycemic field, the effect of this particular substitution could not be predicted. In fact, the GB script encourages the average person skilled in the art 25 not to attempt spiroalkane substitution instead of gem dialkyl substitution, since the preferred compounds of the GB script are stated to be the compounds in which R3 and R4 are both hydrogen (cf. , page 2, lines 43-46), and not the alkyl-substituted compounds.

The novel compounds of the present invention are pyrimidoindoles which are characterized in that they are of the general formula DK 169549 B1 2

R1 .OH

5 J ^ ~ N ^ G

ΈΓ in which R represents lower alkyl, optionally substituted phenyl, optionally substituted naphthyl, an optionally substituted furyl, thienyl, pyridyl, indoly1 or benzothienyl group or a group of the formula R30-B- [wherein- R 30 is (lower) alkoxy, phenyl (lower) alkoxy, substituted phenyl (lower) alkoxy or hydroxy, and B is a lower alkyl chain optionally containing one double or triple double bond], R1 and R2 which may be the same or different, each means hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen (lower) alkyl, halogen, amino or mono- or di (lower) alkylamino, and A together with the carbon to which it is attached, means a 5-, 6- or 7-20 membered saturated carbocyclic ring, wherein the term "lower" means that the group in question contains 1-6 carbon atoms and the term "substituted" means substituted by hydroxy, lower alkyl, lower alkoxy, halogen (lower) alkyl, halogen, amino or mono- or di (low) re) alkyl-amino, or are pharmaceutically acceptable acid addition salts thereof.

The term "lower" as used herein means, as mentioned above, that the group referred to contains 1-6 carbon atoms. Preferably such groups contain from 1 to 4 carbon atoms. A lower alkyl group may e.g. be methyl, ethyl, propyl or butyl, and a lower alkoxy group may e.g. be methoxy, ethoxy, propoxy or butoxy.

Preferably R represents lower alkyl, optionally substituted phenyl, optionally substituted naphthyl or an optionally substituted furyl, thienyl, pyridyl, indolyl or benzothienyl group. R can e.g. Means phenyl, naph- ^ ------ DK 169549 B1 3 thyl or furyl, thienyl, pyridyl, indolyl or benzothienyl, each of which may be substituted or unsubstituted by the substituents mentioned under the definitions for R1 and R2; preferred substituents are halogen, e.g. fluorine, chlorine or bromine, lower alkyl, e.g. methyl, ethyl, propyl or butyl, lower alkoxy, e.g. methoxy, ethoxy, propoxy or butoxy, and halogen (lower) alkyl, e.g. trifluoromethyl. Preferably, R is phenyl optionally substituted as mentioned above, or lower alkyl, e.g. Butyl, but especially phenyl or halophenyl.

Preferred examples of R 1 and R 2 are hydrogen, lower alkyl, e.g. methyl, ethyl, propyl and butyl, lower alkoxy, e.g. methoxy, ethoxy, propoxy and butoxy, halogen (lower) alkyl, e.g. trifluoromethyl, and halogen, e.g. chlorine and 15 bromine.

When R 30 represents a substituted phenyl (lower) alkoxy group, the phenyl group is e.g. substituted with the substituents defined above in connection with R1 and R2. R30 can e.g. be an optionally substituted benzyloxy group.

Examples of suitable R 30 -B groups are 3- or 4-methoxybutyl, 4-ethoxybutyl, 3-methoxy-2-methylpropyl and 3-hydroxy-1-propynyl.

Examples of preferred compounds of the invention are the following: 2 ', 3', 4 ', 10'-tetrahydro-10'-hydroxy-10'-phenyl-spiro [cyclohexane-1,3'-pyrimido (1,2-a ) indole], 2, 3, 4, 101-Tetrahydro-10 '-hydroxy-10' -phenyl-spiro [cycloheptane-1,3'-pyrimido (1,2-a) indole), 2 , 10 '-tetrahydro-101-butyl-10 * -hydroxy-spiro [cyclohexane-1,3'-pyrimido (1,2-a) indole], 2,3-3,4,101 -tetrahydro-10 * -hydroxy 10 '-phenyl-spiro [cyclopentane-1,3'-pyrimido (1,2-a) indole], and the pharmaceutically acceptable salts thereof.

The process according to the invention for the preparation of UK 9569549 bl 4 of the present compounds of formula I is characterized by the characterizing part of claim 8.

Thus, the compounds of the present invention can be prepared by a process in which a ketone of the general formula "WV \ 10

R

wherein R 1, R 2 and A have the above meanings are reacted with an organometallic compound containing a group R 4 which means lower alkyl, optionally substituted phenyl, optionally substituted naphthyl, an optionally substituted furyl, thienyl, pyridyl, indolyl or benzothienyl group, or a group of formula R3'-O-B- wherein R3 'means 20 (lower) alkoxy, phenyl (lower) alkoxy, substituted phenyl (lower) alkoxy or protected hydroxy selected from tetrahydropyranyloxy, trialkylsiloxy or benzyloxy, and B has the aforementioned meaning and, when R3'-O- is a protected hydroxy group, the protecting group is removed to give a product wherein R-O is hydroxy. The organometallic compound 4 may e.g. be a Grignard reagent of formula R MgY, wherein R is as defined above and Y is halogen or an alkali metal compound such as a lithium derivative of formula R Li, e.g. phenyl. The reaction with the organometal compound is generally carried out in an inert organic solvent.

The ketones of general formula (II) may be prepared by known methods, e.g. those in GB Publication No. 1,366,133. A substituted isatin 35 of the general formula - - ------ DK 169549 B1 5

J

vw '

R2 CH -, - C-CN

2Q

1 2 in which R, R and A have the above meanings, and X is a protected oxo group such as a catalyzed oxo group, e.g. ethylene ketal, propylene ketal or dimethoxy, e.g. hydrogenated, e.g. in the presence of a hydrogenation catalyst to give an amine of the general formula 15 R 1

Vy. <iv) CH_CCH ~ NH0 20 2 2 1 2 in which R, R, A and X have the above meanings. The amine can be cyclodehydrated to a compound of the general formula 25 in R '1 2 in which R, R, A and X have the meanings given above. The amine may e.g. cyclodehydrated by heating in an inert organic solvent.

In general, the substituted isatin of general formula (III) can be hydrogenated to the compound of formula (V) without isolating the intermediate amine of the general formula (IV).

The compound of formula (V) can be converted to the ketone of formula (II) by releasing the protected keto group, e.g. by hydrolysis of a ketalized oxo-5 group.

The substituted starting isatin of formula (III) can be e.g. is prepared by the fact that a 3-halo-propanitrile of the general formula 10 NCx2 / CH2Hal (VI)

Q

in which A has the meaning given above and Hal means chlorine or bromine, is condensed with a compound of the general formula

') 3 CC

ir in which R and R have the above meanings and Y means oxo or protected oxo and that when Y means oxo, the oxo group of the resulting product is protected. The condensation may be carried out in the presence of a base, e.g. potassium tert.butoxide or sodium or potassium hydride, in a solvent, e.g. dimethyl sulfoxide, dimethyl furanamide or N-methyl-2-pyrrolidone. The 3-halogenopropane nitriles can be prepared by known methods or by condensation of a corresponding 2-substituted ethanitrile with bromochloromethane, dibromomethane or dichloromethane in the presence of a non-nucleophilic strong base such as lithium diisopropylamide.

DK 169549 B1 7

An alternative method for preparing the compounds of the invention is cyclodehydration of an indole derivative of the general formula 5

V .-- OH

In (VIII) 10 R2 / X ch -c-ch2nh2 va '1 2 in which R, R, R and A have the meanings given above.

The compound of general formula (VIII) in its free base form or as an acid addition salt thereof can be cyclodehydrated to the compound of general formula (I) e.g. by heating in an inert organic solvent. The solvent may e.g. may be 20 xylene or o-dichlorobenzene and the heating may be carried out at reflux temperature. The cyclization is preferably carried out in the presence of a catalytic amount of an acidic catalyst, e.g. p-toluenesulfonic acid or benzenesulfonic acid.

25

The indole compounds of the general formula (VIII) and their acid addition salts can be prepared by hydrogenating a nitrile compound of the general formula

30 R1 v R

--OH

(IX)

R CHoCtCN

w 35 DK 169549 Bl 8 1 2 in which R, R, R and A have the above meanings.

The hydrogenation may be carried out in the presence of a hydrogenation catalyst. Elevated temperatures and pressures can be used. However, if the compound of formula (IX) contains substituents R1 and R2, e.g. For halogen atoms which are prone to being affected by high hydrogenation conditions, hydrogenation should be carried out under mild conditions. For example, a nickel catalyst such as Raney nickel, e.g. Raney nickel W2 (cf. Org. Syn. Coll., Vol. III, 1955, 181), e.g. in the presence of ammonia and ethanol, and the hydrogenation can be carried out at relatively low pressures, e.g. at a pressure of approx. 2.8 kg / cm 2, and temperatures e.g. ca. 40-50 ° C.

The intermediate of formula (VIII) is generally not isolated from the reaction medium, and by hydrogenation of the nitrile of formula (IX) the compounds of the invention are obtained directly.

0 Π

The nitrile compounds of the general formula (IX) may be prepared by an oxindole of the general formula

1 R

XN - OH

RΗ (X) 30 in which R R, R og and have the meanings given above are condensed with a chloropropannitrile of the above general formula (VI) in the presence of a base.

In a further process for preparing the compounds of the invention, a compound of the general formula is cyclized.

Vv + - 5 Le jl λκ (xi>

2/2 / - NH-CH 2 C-CH, Z

R 2 () 'A' 10 or an acid addition salt thereof, in which formula R, R, R and A have the above meanings and Z means a halogen atom, preferably chlorine. The process can be carried out as described in GB patent specification 1,450,543.

In a further process for preparing the compounds of the invention, an indole of the general formula rV r is condensed

pCη - OH

20 I ... I (XII) N NH 2 • in 2 wherein R, R and R have the above meanings, with a dihaloalkane of the general formula

Hal-CH2 * -C-CH2- Hal1 y 30 in which A has the meaning given above and Hal and Hal1 individually mean chlorine, bromine or iodine. The process can be carried out as described in GB Patent No. 1,427,066.

If the compounds of the invention in the above processes are obtained as acid addition salts, the free bases can be obtained by making solutions of the acid addition salts basic, if the product of the process, on the other hand, is a free base, an acid addition salt can be obtained, in particular a pharmaceutically acceptable acid addition salt, by dissolving the free base in a suitable organic solvent and treating the solution with an acid in accordance with conventional methods of preparing acid addition salts from base compounds.

Examples of acid addition salts are those formed from inorganic and organic acids, e.g. sulfuric, saline, hydrogen bromide, phosphorus, wine, fumaric, maleic, lemon, vinegar, ant, methanesulfonic and p-toluenesulfonic acids.

The compounds of the invention have at least one asymmetric carbon atom and can therefore exist in various stereochemical forms. The stereochemical forms can be separated or isolated by standard methods. Resolution of a racemic end product or intermediate may e.g. is performed by known methods so that the product is obtained as an optically active enantiomorphic compound.

The compounds of the present invention have pharmacological activity. The compounds have e.g. usually hypoglycemic activity and are therefore valuable in the treatment of diabetes. The compounds of this invention have been tested for hypoglycemic activity by a standard method by which the compounds are administered to rats and blood glucose concentration is determined before administration and at different times after dosing. Upon examination of tetrahydro-101-hydroxy-10'-phenylspiro [cyclohexane-1,3'-pyrimido [1,2-a] indole], a representative compound of the invention, by this method at 100 mg / kg p.o. For example, blood glucose concentration was found to be 76% and 65% relative to control animals (i.e., rats given vehicle alone) at 2 hours and 4 hours after administration, respectively. The compounds of the following Examples 3, 4, 35 and 5 (b) have been tested by the same method and give a significant decrease in plasma glucose concentration both 2 and 4 hours after the administration of a dose of 100 mg per day. kg.

The present invention further provides a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof for use as a hypoglycemic agent for mammals.

The invention also relates to a pharmaceutical composition containing a compound of the general formula (I) or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable carrier. Any pharmaceutical carrier which is already known can be used for the preparation of the pharmaceutical composition. In such a composition, the carrier is generally a solid or liquid substance or a mixture of a solid and a liquid substance.

Solid form preparations include powders, granules, tablets, capsules, e.g. hard and soft gelatin capsules, suppositories and pessaries. For example, a solid support may e.g. be one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, lubricants, compression auxiliary binders or tablet solvents; said carrier may also be an encapsulating material.

In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is blended with a carrier having the necessary compression properties in appropriate proportions and compressed to the desired shape and size. The powder products and tablets preferably contain up to 99%, e.g. from 0.03 to 99%, preferably from 1 to 80% of the active ingredient. Suitable solid carriers are e.g. calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinyl-pyrrolidine, low melting waxes and ion exchange resins.

The term "preparation" means the formulation of an active ingredient with encapsulating material as carrier 5 to obtain a capsule in which the active ingredient (with or without other carriers) is enclosed by the carrier thus associated therewith. Powder bags are also included.

Liquid form preparations include, e.g. solutions, suspensions, emulsions, syrups, elixirs and pressurized preparations. The active ingredient may e.g. dissolved or suspended in a pharmaceutically acceptable liquid carrier, e.g. water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical additives, e.g. solvents, emulsifiers, buffers, preservatives, sweeteners, flavors, suspending agents, thickening agents, dyes, viscosity regulators, stabilizers or osmo regulators. Examples of suitable liquid carriers for oral and parenteral administration are water containing, in particular, additives such as those mentioned above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution, alcohols comprising monovalent alcohols and polyhydric alcohols, e.g. glycerol and glycols, and derivatives thereof, and oils, e.g. fractionated coconut oil and arachin oil. For parenteral administration, the carrier may also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form preparations for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions or suspensions may e.g. is used for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions may also be administered intravenously. When the compound is orally active, it can be administered orally either in the form of a liquid or solid preparation.

The pharmaceutical composition is preferably in unit dosage form, e.g. such as tablets or capsules. In such a form, the composition is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage forms may be packaged preparations, e.g. packed powders, 10 small medicine bottles, ampoules, pre-filled syringes or bags containing liquids. The unit dosage form can e.g. may be the capsule or tablet itself, or it may be a suitable number of any of these compositions in packaged form. The amount of the active ingredient in unit doses of the composition can be varied or regulated from 0.5 mg or less to 750 mg or more, depending on the particular needs and activity of the active ingredient.

The invention also relates to the compounds when there is no carrier and the compounds are in unit dosage form.

The invention is further explained in the following examples.

25 1 35 5 DK 169549 B1

Example in 14 31,4'-Dihydrospiro [cyclohexane-1,3 * -pyrimido (1/2-a) indo 1-101 (2Ή) -one] (a) 1- [1 * - [2 * (3) Ή) -oxospiro (1,3-dioxolane) -2,3'-indolyl] -methylcyclohexane-carbonitrile 1.91 g spiro [1,3-dioxolane) -2,3µl-21-21 (3'H ) -one] is added portionwise to a stirred solution of 1.34 g of potassium tert-butoxide in 20 ml of dry DMSO under nitrogen. After 10 minutes, 1.96 g of 1-chloromethylcyclohexanecarbonitrile is added dropwise and the solution is heated at 130 ° C for 24 hours. The solution is cooled, poured into 100 ml of ice water and stirred vigorously for 18 hours. The solid I5 is separated, dried and recrystallized from propan-2-ol to give 1.4 g of the title compound, m.p. 130-130.5 ° C.

C 18 H 20 N 2 O 3: Calculated: C = 69.2%, H = 6.45%, N = 9.0%; Found: C = 69.0%, H = 6.7%, N = 8.8%.

(b) 2 ^ 3 ^ 4 ^ 101 -Tetrahydro (1,3-dioxolane) -2-spiro-101-pyrimido [1,2-a] indole-3'-spirocyclohexane 100 ml ethanolic ammonia and one spatula Raney nickel 25 is added to a solution of 1.25 g of 1- [11 - [21 (31H) -oxospiro (1,3-dioxolane) -2,3'-indolyl] methylcyclohexane carbonitrile in 100 ml of ethanol. The mixture is hydrogenated at 50 ° C at a pressure of 4-5 atm. (about 3.9 x 10 x * - 4.9 x 10 ^ Pa) for 2 hours. After cooling to room temperature, the mixture is filtered through diatomaceous earth and the solution is concentrated in vacuo to give 1.23 g of the crude product. The product is redissolved in 60 ml of ether, filtered through diatomaceous earth and concentrated in vacuo. The product is recrystallized from hexane to give 0.36 g of a first portion of the title compound as the free base, m.p. 71-107 ° C.

DK 169549 B1 C18H22N2 ° 2: Calculated: 0 = 72.45% / H = 7.45%, N = 9.40%;

Found: 0 = 72.30%, H = 7.55%, N = 9.56%.

Additional material is obtained by mother liquor chromatography on SiO 2 eluting with EtOAc.

(o) 3 ^ 41-Dihydrospiro [cyclohexane-1,31-pyrimido [1,2-a] indole-101 (2'H) -one]

A solution of 4.4 g of the compound of Example 10 (b) in 3 ml of hexane is added dropwise to 25 ml of concentrated H 2 SO 2 at 30 ° C. The solution is kept at room temperature and poured on ice after 1 hour. The solution is made basic with concentrated aqueous ammonia and at pH = 7 a brown precipitate is obtained. The Op-I5 solution is decanted and further basified with concentrated aqueous ammonia to pH = 9. The precipitate is separated by filtration, washed with aqueous ammonia and dried in vacuo. A solution of the solid in EtOAc is passed down a silica column and the solvent is evaporated to give 1.4 g of the title compound as crystals of m.p. 138-143 ° C.

C16H18N201 / 4H2O: Calculated: C = 75.6%, H = 7.1%, N = 11.0%;

Found: C = 74.5%, H = 7.3%, N = 10.8%.

25 1 35

Example 2 DK 169549 B1

ISLAND

16 2 ', 31,41,101-Tetrahydro-101-hydroxy-101-phenylspiro [cyclohexane-1,3'-pyrimido (1,2-a) indole] Bromobenzene (10 drops; from 2.6 g) is added dropwise to 0.38 g of stirred magnesium shavings in 10 ml of diethyl ether under nitrogen. When the reaction begins, 3 ml of a solution of the residual bromobenzene in diethyl ether is added dropwise to maintain reflux. The mixture is heated at reflux until some magnesium is left and cooled, then a solution of 1.4 g of 3 ', 4'-dihydro-spiro [cyclohexane-1,3'-pyrimido (1,2-a) is added dropwise. indole-10 (2H) on] in 20 ml of dichloroethane. After 1 hour, the reaction mixture is poured into 100 ml of water and extracted with 2 x 100 ml of chloroform and the chloroform extracts are combined, dried (MgSO 4) and evaporated under reduced pressure to give a solid. Trituration of the solid with diethyl ether, followed by recrystallization from ethyl acetate, gives 0.85 g of the title compound. Ethereal hydrogen chloride is added to a solution of the title compound in propan-2-ol to give 0.55 g of the title compound in the form of the hydrochloride as a precipitate of white crystals 25, m.p. 273-274 ° C (Sunday).

C 22 H 24 N 2 ° HCl: Calculated: C = 71.6%, H = 6.8%, N = 7.6%;

Found: C = 71.3%, H = 7.1%, N = 7.5%. 1 35

Example 3 DK 169549 B1

ISLAND

17 21,3 ', 4', 1Q'-Tetrahydro-101-hydroxy-101-phenylspiro [cycloheptane-11 '- pyrimido (1,2-a) indole] 5 (a) 1- [1- (3 -Hydroxy-2 (3H) -oxo-3-phenylindolyl) ethyl] -cycloheptanecarbonitrile 9.0 g of 3-hydroxy-3-phenylindol-2 (1H) is added portionwise to a stirred solution of 4.9 g of potassium 10-tert. butoxide in 100 ml of dimethyl sulfoxide under an atmosphere of nitrogen. After 10 minutes, 6.9 g of 1-chloromethylcycloheptanecarbonitrile are rapidly added. The solution is heated to 130 ° C for 18 hours, cooled and poured into 500 ml of water. The aqueous mixture is extracted with 3 x 200 ml of diethyl ether and the organic extracts are dried (MgSO 4) and evaporated in vacuo to ca. half the volume to give 1.94 g of a white precipitate of the title compound. Further washing of the drying agent with chloroform and evaporation in vacuo afforded an additional 1.8 g of the title compound.

A small sample is recrystallized from propan-2-ol; mp. 202.5-203.5 ° C.

C23 H24 N4 O2.1 // 4H2 O: Calculated: C = 75.7%, 06.8%, N = 7.7%; Found: 076.1%, 06.8%, N = 7.5%.

(b) 2 ^ 3 ^ 4 ^ 101 -Tetrahydro-10 '-hydroxy-101-phenyl-spiro [cycloheptane-1,3'-pyrimido (1,2-a) indole] 4.0 g of a mixture of the compound of 30 Example 3 (a) and 1 small spoonful of Raney nickel in 200 ml of 50% saturated ethanolic ammonia are heated at 50 ° C under hydrogen atmosphere (at a pressure of about 3.51 kg / cm, about 3 x 10 Pa) for 7 hours. The mixture is cooled and filtered through diatomaceous earth and the filtrate is evaporated under reduced pressure to give 3.6 g of a rubber material. When triturating rubber material

ISLAND

With EtOAc, 2.43 g of a solid is obtained. The filtrate is evaporated under reduced pressure to give an oil which is triturated with EtOAc to give 0.43 g of a solid. The solid from the first trituration (2.43 g) is chromatographed (basic A₂O₂; CHClg) and the rubber material is triturated with EtOAc to give 1.45 g of a solid. A solution of 1.88 g of the combined solids in MeOH is treated with ethereal hydrogen chloride and evaporated under reduced pressure to give an oil which is triturated with Et 2 O to give 1.93 g of the title compound as the hydrochloride with mp. 267 ° C (Sunday).

C 22 H 26 N 2 ° HCl: Calculated: C = 71.8%, H = 6.8%, N = 7.3%; Found: C = 72.2%, H = 6.9%, N = 7.5%.

Example 4 21,3 ', 4 1,101-Tetrahydro-101-butyl-10'-hydroxyspiro-20 [cyclohexane-1,31-pyrimido (1,2-a) indole] (a) 3.4 g of 3-butyl 3-hydroxyindole-2 (3H) -one is added portionwise to a solution of 1.9 g of potassium tert-butoxide in 30 ml of dry deoxygenated dimethyl sulfoxide. To this is added 3.2 g of 1-chloromethylcyclohexanecarbonitrile.

The mixture is heated to 130 ° C for four days and then poured onto ice. By extraction with ethyl acetate, washing with water, drying (MgSO 4) and evaporation in vacuo, an crude oil is obtained which is purified by chromatography on silica eluting with ether. Crystallization from a mixture of ethyl acetate and hexane and recrystallization from cyclohexane yield 5.4 g of 1- [1- (3-butyl-3-hydroxy-2 (3H) -oxo-indolyl) methyl] cyclohexanecarbonitrile as crystals with m.p. 124-125 ° C.

(B) The crystals of Example 4 (a) are hydrogenated

ISLAND

In 200 ml of saturated ethanolic ammonia with Raney nickel 2 under hydrogen atmosphere (at a pressure of about 2.81 kg / cm; about 2.7 x 10 Pa). After removal of the catalyst, evaporation in vacuo and trituration with ethyl acetate, there are obtained 2.0 g of the title compound as colorless crystals, m.p. 192-195 ° C.

C 20 H 28 N 2 ° HCl * 2 // 3 C 3 H 80: Calculated: C = 67.9%, H = 8.9%, N = 7.2%;

Found:: C = 67.9%, H = 9.3%, N = 7.2%.

10

Example 5 2 3 3 4 4 101 -Tetrahydro-101-hydroxy-10 * -phenylspiro [cyclopentane-1,3 * -pyrimido (1,2-a) indole oil (a) 11.50 g of 3-hydroxy 3-Phenylindole-2 (3H) -one is added portionwise to a stirred solution of 6.30 g of potassium tert-butoxide in 125 ml of dry, deoxygenated dimethyl sulfoxide under nitrogen. After 0.5 hour, 7.18 g of 1-chloromethylcyclopentacarbonitrile are added and the solution is heated at 120 ° C for 17 hours, cooled to room temperature and poured into 500 ml of water. The mixture is extracted with ethyl acetate (3 x 250 ml). The extracts are washed with 100 ml of water, dried (MgSO 4) and evaporated under reduced pressure to give a rubber material which is triturated with diethyl ether to give 9.49 g of 1- [1- (3-hydroxy-2 (3H) ) -oxo-3-phenylindolyl) methyl] -cyclopentanecarbonitrile as a crystalline solid, m.p. 155-157 ° C.

C 21 H 20 N 2 O 2: Calculated: C = 75'9% H = 6.1%, N = 8.4%;

Found: C = 75.6%, H = 6.25, N = 8.2%.

(b) A mixture of 8.3 g of 1- [1- (3-hydroxy-2 (3H) -oxo-35-phenylindolyl) methyl] cyclopentanecarbonitrile and 2 spatial spoonfuls of Raney nickel in 200 ml of 50% saturated ethanolic DK The ammonia is heated at 50 ° C under hydrogen atmosphere (at a pressure of about 3.51 kg / cm? About 3 x 10 Pa) for 18 hours. The mixture is cooled, filtered through diatomaceous earth and evaporated under reduced pressure. and a solid is obtained which is purified by trituration with ethyl acetate, chromatography (basic Al 2 O 4 chloroform) and trituration with ethyl acetate to give 5.9 g of the title compound.

A solution of the title compound in methanol 10 is treated with ethereal hydrogen chloride and evaporated under reduced pressure to give a solid which is washed with diethyl ether and air dried to give 6.2 g of the title compound as the hydrochloride with m.p. 263-264 ° C (Sunday).

HCl: Calculated: C = 71.1%, H = 6.5%, N = 7.9%;

Found: C = 70.7%, H = 6.7%, N = 7.9%.

Example 6 (-) and (+) - 2 *, 3 ', 4'DO'-tetrahydro-10'-hydroxy-10'-phenylspiro [cyclohexane-1,31-pyrimido (1,2-a) indole] 40.44 g (100.0 mmol) (-) - di-p-toluoyl-L-tartaric acid is added rapidly and portionwise to a stirred suspension of 33.25 g of the compound of Example 2 in 1 liter of acetone. The clear solution is stirred at room temperature for 15 hours and the crystalline precipitate is separated by filtration, washed with 2 x 50 ml of acetone and dried to give 31.64 g of (-) - 2 ^ 3 ^ 4 ^ 10 ^ 30 tetrahydro 101-hydroxy-10'-phenylspiro [cyclohexane-1,31-pyrimidod, 2-a) indole] as the (-) - di-p-toluoyl tartrate with m.p. 149 ° C (Sunday). [α] D -93 ° (about 0.2% in EtOH).

The combined filtrate and washings are concentrated in vacuo to give a slightly brown crystalline residue which is converted to the free base.

23.05 g (570 mmol) of (+) - di-p-toluoyl-D-tartaric acid are added portionwise and rapidly to a stirred suspension of the free base enriched with (+) enantiomer in 570 ml of acetone. The solution is stirred at room temperature for 15 hours and the crystalline precipitate is separated by filtration, washed with 2 x 50 ml acetone and dried to give 33.60 g (+) - 2 ', 3', 4 ', 10'- tetrahydro-10'-hydroxy-10'-phenylspiro [cyclohexane-1,3'-pyrimido (1,2-a) indole] as the (+) - di-p-toluoyl tartrate with 10 m.p. 149 ° C (Sunday). [α] D + 95 ° (about 0.2% in EtOH).

Preparation of the hydrochlorides

The hydrochloride of each enantiomer is prepared by converting each di-p-toluoyl tartrate to the free base. The separated free bases are separately suspended in 1 200 ml of absolute ethanol and the suspension is acidified with ethereal hydrogen chloride. The solution of each hydrochloride is concentrated in vacuo and the crystalline product is separated by filtration, washed with 2 x 20 ml of ethanol and dried under high vacuum at 50 ° C for 15 hours to give, in two portions, 11.57 g of the hydrochloride of the (-) enantiomer with m.p. 271 ° C (Sunday). [a] D-225 ° (about 0.2% in CHCl3) (C22H24N2O * HCl: Calcd; C = 71.65%, H = 6.85%, N = 7.60%;

Found: C = 71.30%, H = 6.85%, N = 7.40%) and 13.51 g of the hydrochloride of the (+) enantiomer with m.p. 269 ° C (Sunday). [α] + 220 ° (about 0.2% in CHCl3).

C22H24N2 ° * HCl: Calculated: C = 71.65%, H = 6.85%, N = 7.60%; Found: C = 71.70%, H = 6.75%, N = 7.45%.

A different amount (about 10%) of each enantiomer is obtained by working up the mother liquor from the starting solutions.

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Claims (10)

1. Pyrimidoindoles, characterized in that they have the general formula 5 RV R ^O »R2 wherein R is lower alkyl, optionally substituted phenyl, optionally substituted naphthyl, an optionally substituted furyl, thienyl, pyridyl, indolyl, or benzothienyl group or a group of formula R 30 -B- [wherein R 30 is (lower) alkoxy, phenyl (lower) alkoxy, substituted phenyl (lower) alkoxy or hydroxy, and B is a lower alkylene chain optionally containing one double or triple bond], R1 and R2, which may be the same or different, each means hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen (lower) alkyl, halogen, amino or mono or di (lower) alkylamino, and A, together with the carbon atom to which it is attached, means a 5-, 6- or 7-membered saturated carbocyclic ring, wherein the term "lower" means that the group in question contains 1-6 carbon atoms, and the term "substituted" means substituted by hydroxy, lower alkyl , lower alkoxy, halogen (lower) alkyl, halogen, amino or mono- or di (lower) alkylamino, or are pharmaceutically acceptable acid addition salts thereof. A compound according to claim 1, characterized in that R is lower alkyl, optionally substituted phenyl, optionally substituted naphthyl or an optionally substituted furyl, thienyl, pyridyl, indolyl or benzothienyl group. A compound according to claim 1, characterized in that R is phenyl or halophenyl. A compound according to any one of claims DK 169549 B1 1-3, characterized in that A means - (CH 2) n - wherein n is 4, 5 or 6. Compound according to claim 1, characterized in that it is 2 ', 31,4', 10'-tetrahydro-10'-hydroxy-101-phenylspiro [cyclohexane-1,3'-pyrimido (1,2 -a) indole or a pharmaceutically acceptable acid addition salt thereof. Compound according to claim 1, characterized in that it is 2 ', 3', 4 ', 10'-tetrahydro-10'-hydroxy-10'-phenylspiro [cyclo-10-heptane-1,3'-pyrimido (1 , 2-a) indole] or 2 1,3 ', 4', 10 '-tetrahydro-10' -butyl-10 '-hydroxyspiro [cyclohexane-1,3'-pyrimido (1,2-a) indole ] or 2 ', 3', 4 ', 10'-tetrahydro-10'-hydroxy-10'-phenylspiro [cyclopentane-1,3'-pyrimido (1,2-a) indole] or a pharmaceutically acceptable acid addition salt thereof. Compound according to claim 1, characterized in that it is (-) - 2 ', 3', 4 ', 10'-tetrahydro-10'-hydroxy-10' - phenylspiro [cyclohexane-1,3'-pyrimido (1,2-a) indole or (+) - 21,31,4 ', 10'-tetrahydro-10 * -hydroxy-10'-phenylspiro-20-cyclohexane-1,3'-pyrimido (1,2 · -a) indole or a pharmaceutically acceptable acid addition salt thereof. Process for the preparation of a compound according to claim 1, characterized in that (a) a ketone of the general formula R2, which R1, R2 and A have the meanings set forth in claim 1, is reacted with an organometallic compound containing an R4-3 residue wherein R4 is lower alkyl, optionally substituted phenyl, optionally substituted naphthyl, or even 4 optionally substituted furyl, thienyl, pyridyl, indolyl, or benzothienyl group, or a group of formula R3'-O-B- wherein R31 is (lower) alkoxy, phenyl (lower) alkoxy, substituted phenyl (lower) alkoxy or protected hydroxy selected from tetrahydropyranyloxy, trialkylsiloxy and benzyloxy, and B has the meaning set forth in claim 1 and, when R 3 '- 0 - is a protected hydroxy group, the protecting group is removed to obtain a product wherein R 3' - 0- is hydroxy or (b) an indole derivative of the general formula 10 R 1 R __OH, ΰΑ, Α. R 2 X CH 2 C-CH-NH-, wherein R, R 1, R 2 and A have those in the meanings given in claim 1 are cyclodehydrated or that (c) a nitrile of the general formula R 1 VS-1-OH <IX) 2 / CH 2 C-CN R 2 (a) in which R, R 1, R 2 and A have the meanings specified in claim 1 are hydrogenated, or that (d) a compound of the general formula R 1 R 'edr ^ nh-ch 2 -c) -ch 2z A RA in which R, R1, R2 and A are as defined in claim 1, and Z is a halogen atom or an acid addition salt thereof cyclized or (e) an indole of the general formula -OH J 2 (XII) 10 K in which R, R 1 and R 2 have the meanings given in claim 1 are condensed with a dihaloalkane of the general formula Hal-CH2-C-CH2-Hal · in which A has the meaning set forth in claim 1, and Hal and Hal 'each mean chlorine, bromine or iodine, after which an emergent base is optionally converted into a pharmaceutically acceptable acid addition salt thereof and / or a racemic product is separated. Pharmaceutical composition, characterized in that it contains a compound according to any one of claims 1-7 in association with a pharmaceutically acceptable carrier. A compound according to any one of claims 1-7 for use as a pharmaceutical composition. 30 35